chr19-623546-A-G

Variant names:

• chr19-623546-A-G
• rs41553913
• NM_005035.4:c.1198T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005035.4(POLRMT):​c.1198T>C​(p.Phe400Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0161 in 1,613,624 control chromosomes in the GnomAD database, including 925 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.046 (433 hom., cov: 33)
  • Exomes 𝑓: 0.013 (492 hom.)
• Consequence: POLRMT NM_005035.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.43
• Publications: 8 publications found

Genes affected

POLRMT (HGNC:9200): (RNA polymerase mitochondrial) This gene encodes a mitochondrial DNA-directed RNA polymerase. The gene product is responsible for mitochondrial gene expression as well as for providing RNA primers for initiation of replication of the mitochondrial genome. Although this polypeptide has the same function as the three nuclear DNA-directed RNA polymerases, it is more closely related to RNA polymerases of phage and mitochondrial polymerases of lower eukaryotes. [provided by RefSeq, Jul 2008]

POLRMT Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 55

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020318627).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLRMT	NM_005035.4	c.1198T>C	p.Phe400Leu	missense_variant	Exon 6 of 21	ENST00000588649.7	NP_005026.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLRMT	ENST00000588649.7	c.1198T>C	p.Phe400Leu	missense_variant	Exon 6 of 21	1	NM_005035.4	ENSP00000465759.2
POLRMT	ENST00000590573.4	c.964T>C	p.Phe322Leu	missense_variant	Exon 4 of 4	3		ENSP00000466504.4
POLRMT	ENST00000590709.3	n.631T>C		non_coding_transcript_exon_variant	Exon 3 of 5	2

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7039 AN: 152142 Hom.: 431 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00922

Gnomad OTH AF: 0.0468

GnomAD2 exomes AF: 0.0183 AC: 4586 AN: 250640 AF XY: 0.0156

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0321

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00328

Gnomad NFE exome AF: 0.00990

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0130 AC: 18980 AN: 1461364 Hom.: 492 Cov.: 34 AF XY: 0.0124 AC XY: 8995 AN XY: 727026

African (AFR) AF: 0.147 AC: 4905 AN: 33474

American (AMR) AF: 0.0130 AC: 580 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 842 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00815 AC: 703 AN: 86254

European-Finnish (FIN) AF: 0.00362 AC: 192 AN: 53006

Middle Eastern (MID) AF: 0.0427 AC: 245 AN: 5740

European-Non Finnish (NFE) AF: 0.00918 AC: 10207 AN: 1111966

Other (OTH) AF: 0.0216 AC: 1304 AN: 60374

GnomAD4 genome AF: 0.0463 AC: 7053 AN: 152260 Hom.: 433 Cov.: 33 AF XY: 0.0442 AC XY: 3288 AN XY: 74450

African (AFR) AF: 0.139 AC: 5796 AN: 41550

American (AMR) AF: 0.0216 AC: 331 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4820

European-Finnish (FIN) AF: 0.00301 AC: 32 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00922 AC: 627 AN: 68010

Other (OTH) AF: 0.0464 AC: 98 AN: 2114

Alfa AF: 0.0157 Hom.: 130

Bravo AF: 0.0530

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.137 AC: 604

ESP6500EA AF: 0.00837 AC: 72

ExAC AF: 0.0206 AC: 2496

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.0100

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		4.4
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.31	T;.
Polyphen		0.18	B;.
Vest4		0.23
MutPred		0.68		Gain of disorder (P = 0.0618);.;
MPC		0.65
ClinPred		0.032	T
GERP RS		4.6
Varity_R		0.74
gMVP		0.67
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41553913; hg19: chr19-623546; COSMIC: COSV73933075; COSMIC: COSV73933075;